Immune Therapy’s Cancer Promise Creates Research Rush

By Naomi Kresge and Robert Langreth -
May 29, 2014

A new class of medicines that help the body’s own immune cells fight tumors could target a wide set of cancers, opening a $35 billion market for Merck (MRK) & Co., Bristol-Myers Squibb Co., AstraZeneca Plc and Roche (ROG) Holding AG.

The drugmakers will use the world’s largest meeting of cancer doctors, the American Society of Clinical Oncology, to stake their claim on the new technology, which aims to interrupt cancer’s ability to switch off immune system cells that might otherwise attack it.

For years, the idea was only seen as usable against a handful of uncommon tumors. Now, new evidence the drugs may work in a wider range of malignancies, advanced in just the last two years, has spurred Merck, Bristol-Myers, AstraZeneca and Roche to begin at least 78 clinical trials. While the research, with more than 19,000 patients, could cost the four companies as much as $1.3 billion, the payoff would be the creation of a new market that Citigroup Inc. (C) analysts have predicted could reach $35 billion a year.

“I have never seen this much enthusiasm collectively for a class of drugs before,” said Asthika Goonewardene, a London-based analyst at Bloomberg Industries. “This is essentially what we call a land grab. There’s opportunity, and everybody is going out to find what that opportunity is.”

One reason for the excitement is that the body’s response to immune therapy tends be long lasting, said Jill O’Donnell-Tormey, chief executive officer of the nonprofit Cancer Research Institute in New York. The belief is that once the immune system is properly activated against an invading cancer, it will remember what a tumor cell looks like, she said.

That theory still needs to be proven across a range of cancers and the therapy is not without side effects, including lung inflammation and a variety of other autoimmune-related events. Still, the idea that cancer can be tamed without brutal chemotherapy or heavy-duty radiation is enticing.

‘Too Late’

Companies know they have to move quickly, said Antoni Ribas, a melanoma specialist at University of California, Los Angeles who has tested Merck’s drug, MK-3475. If they don’t, “somebody else will do it and then it will be too late,” he said.

The turnaround in interest was sparked in part by a finding presented by Bristol-Myers two years ago at the same cancer meeting. The company reported then that its drug, nivolumab, shrank tumors in 28 percent of melanoma patients, 27 percent of people with kidney cancer and 18 percent of those with advanced lung cancer. It was a surprising finding that suggested use of immune therapy may be broadened beyond melanoma, its initial target, to other more common cancers.

Since then, trials have sprung up like mushrooms, with more than 70 presentations on the immune therapies expected during the oncology meeting in Chicago starting May 30.

Off Switch

The theory behind the therapies is fairly simple. Under normal circumstances, a protein called PD-1 acts as a switch to shut off the action of attack cells within the immune system that respond when the body is attacked by a foreign invader. It turns out that some cancer cells get around that with a unique ability to flick the off switch.

The drugs being developed work by either binding to the PD-1 protein to protect it from manipulation by tumor cells, or by hitting a related protein called PD-L1 that some tumor cells deploy to trigger the PD-1 switch.

Merck’s push into the new therapy field shows how excitement around the strategy has grown.

The Whitehouse Station, New Jersey-based company initially began its work in immunotherapy in 2011 with a small trial on a handful of patients. The early results, especially in melanoma, were so intriguing, though, that the drugmaker quickly expanded it to involve 1,300 patients with various malignancies, including melanoma and lung cancer.

‘Kept Adding’

“It was going to be your typical first-in-man study,” said Alise Reicin, a Merck & Co. executive overseeing the U.S. company’s development program. “We had a small cohort planned in melanoma. But as we started very early on to see responses, over time we just kept adding.”

Results from the melanoma testing are already part of the company’s application for marketing approval for its MK-3475 drug for advanced melanoma patients who have already tried another immune drug. The application is being reviewed by the U.S. Food and Drug Administration, with a decision expected by the end of October. Merck will report the melanoma data at ASCO, along with data from its testing against head-and-neck cancer.

Cancer doctors at the meeting will also see data from research on a drug made by Basel, Switzerland-based Roche in bladder cancer, as well as information on how well melanoma patients did over the long term when treated with a combination of two immune therapy drugs made by New York-based Bristol-Myers. (BMY)

Bristol-Myers is building on what it learned developing Yervoy, a melanoma drug approved three years ago that hit a different off-switch for immune cells, according to Michael Giordano, a senior vice president who worked on both Yervoy and nivolumab, the company’s PD-1 product.

Time, Patience

In developing Yervoy, Bristol-Myers learned how to manage immune therapy’s side effects and how to design a clinical trial to best show the drug’s lasting benefits, Giordano said. That took time and patience, he said.

If you stop too soon, “you don’t have the proper number of patients and you won’t conduct the right kind of clinical trial,” he said.

Pfizer once was testing a similar drug to Yervoy called tremelimumab, but six years ago it halted a large trial of the drug, and later licensed many of the rights to AstraZeneca. (AZN) Some doctors say Pfizer, which still has rights to the drug when used with cancer-attacking vaccine therapy, may have given up too soon. Pfizer isn’t currently testing the drug, according to a government clinical trials database.

Bristol-Myers now is testing nivolumab in 35 trials, including more than 7,000 patients, “probably the largest development program ever done in oncology for an experimental agent,” said Fouad Namouni, a Bristol-Myers vice president.

Running big trial programs is an expensive business. The longer patients live, the longer the process lasts and the more expensive it becomes, opening the temptation to close down development when hurdles develop.

The cost of early-phase testing in cancer generally ranges from $25,000 to $40,000 per patient, with mid-stage trials running $60,000 to $80,000, said Greg Dombal, chief operating officer for Boston-based Halloran Consulting Group. A final-phase trial can cost at least $100,000 a patient for recruitment, genetic tests, establishing new databases and monitoring progress with scanning equipment.

Rising Costs

“Your up-front decision-making process has a lot of impact on whether your program will be successful,” said Niko Andre, Roche’s head of medical affairs in oncology. The immune therapy race doesn’t have just one finish line, he said by telephone, but is rather the start of some of “the broadest and widest development programs for years to come.”

A second round of immune-drug testing will include the development of combination therapies designed to improve the response rates and keep patients alive longer. Combinations also may come into play against tumors that don’t usually have a lot of active immune cells working against them, researchers said.

Bristol-Myers, Merck & Co., AstraZeneca and Roche aren’t alone in the field. Other companies are further behind or have announced smaller programs.

For instance, Merck KGaA (MRK), a Darmstadt, Germany-based drugmaker that isn’t affiliated with the U.S. company, has two early-stage patient trials for a PD-L1 drug. Meanwhile, Switzerland’s Novartis AG (NOVN) also bought into PD-1 field in February with the acquisition of Cambridge, Massachusetts biotech CoStim Pharmaceuticals Inc. Novartis may start patient trials of a CoStim immune drug as early as next year, and jump straight to a final-phase study the following year, though no final decision has been made, said Alessandro Riva, the company’s interim head of oncology.

Susan Galbraith, AstraZeneca’s head of small-molecule oncology, said there may be less urgency to be first in the field since companies will quickly find themselves collaborating with others to develop the most effective combinations.

“This is a new class of agents that’s going to work in multiple different cancers and in multiple different combinations,” Galbraith said by telephone. “To say you’re too late because you’re a year behind the initial leaders is naive, because we’re all going to be working on this together.”